Giardia lamblia is the most common protozoan cause of diarrhea in the world. It infects ~500 million people worldwide resulting in nutrient malabsorption which can lead to cognitive developmental defects in children. Mechanisms of pathogenesis in giardiasis are poorly understood, hindering efforts to both treat and prevent this disease. Data suggest that immune responses contribute to pathology by inducing shortening of the microvilli on intestinal epithelial cells that provide an enhanced surface area for nutrient absorption. Our hypothesis is that immune responses affect the epithelial cell cytoskeleton through post-translational regulation of the adaptor protein ezrin. Ezrin links the plasma membrane to actin microfilaments and is essential for proper formation of microvilli. This proposal will test determine if immune responses against the parasite lead to changes in the function of ezrin in epithelial cells using mouse and in vitro models. The role of key signaling pathways and the ability to modulate these pathways with pharmacologicals will also be investigated. PUBLIC HEALTH RELEVANCE: Giardia is the most common protozoan cause of diarrhea in the US and is also considered a Biodefense Category B threat agent. The studies in this proposal will improve public health by examining how this infection causes nutrient malabsorption that can lead to defects in cognitive development. This information will provide new strategies for treating common diseases like celiac disease and inflammatory bowel disease as well as diarrheal diseases like giardiasis.